This application is for the first renewal of the Dana-Farber/Harvard SPORE in Breast Cancer, funded October 1, 2000. This SPORE is a component of the Breast Cancer Program in the Dana-Farber/Harvard Comprehensive Cancer Center (DF/HCC), and includes investigators from all major DF/HCC sites, Harvard University and MIT. Six Projects are proposed: Project 1 seeks common molecular pathways shared by basal-like and BRCA1 -linked cancers, and proposes a preoperative clinical trial in HER2-and ER-negative cancers. Project 2 will improve the treatment of HER2-positive cancer by searching for new targets and new drugs to use in combination with trastuzumab. Project 3 examines the response of ER-positive cancers to aromatase inhibitors, focusing on the role of coactivators and receptor occupancy of ER target sequences. Project 4 addresses the conundrum of metastasis using genomic approaches to study human primary and metastatic disease. Project 5 examines the role of tumor - stromal interactions in the early breast neoplasia, and seeks diagnostic and therapeutic targets that are active in this interaction. Project 6 will combine functional studies in cells and tissues with population-based research to seek alleles of kinase genes associated with increased risk. These Projects will be supported by the following Core Resources: Tissue and Pathology, providing a range of tissues and services;Clinical Studies, managing the interface between research and patients (recruitment, consent, and registration);Cohort Studies, managing and maintaining databases of research and clinical resources;Biostatistics, providing statistical consultation to SPORE investigators;and Bioinformatics to manage large genomic data sets and provide initial consultation to investigators seeking analytical help. The Harvard SPORE will devote 13% of its direct research costs to Career Development and Developmental Projects, and proposes selection and evaluation processes. The Communication, Planning and Administration Core will continually improve the SPORE by evaluating, planning and modifying our research to maximize our impact on breast cancer.